Citations

Abstract A macro-driven Lotus 1-2-3 ™ template is described that allows the rapid generation of labels. Use of this template allows flelixbility in the design of labels and can provide labels during computer “down time”.

Stroke subtype classification, applying standard criteria to clinical data, can reduce the heterogeneity of ischemic stroke for genetics studies. To date, most of the replicated genetic loci for ischemic stroke appear subtype-specific. Increasing homogeneity of phenotype comes with a trade-off in sample size, which influences the potential for successful identification of new loci. We estimated genetic associations using the union and intersection of two widely used stroke subtyping systems to assess the influence of sample size and homogeneity on test statistics. Methods: The Stroke Genetics Network (SiGN) study used both the Causative Classification of Stroke (CCS) and the Trial of ORG10172 Acute Stroke Trial (TOAST) classification systems. The CCS generates both a causal and a phenotypic subtype. Using all available data from case-control strata from the a previously performed GWAS, we focused on three main stroke subtypes: cardioembolic (CE), large artery atherosclerosis (LAA), and small artery occlusion (SAO). We estimated genetic associations with the union of the two CCS outputs and TOAST ( eg called CE by at least one method) and the intersection ( eg called CE by all three methods). Our modelling approach included a fixed-effects meta-analysis, i.e. pooling stratum specific estimates from logistic regression models using 10 principle components to account for genetic ancestry responsible for population stratification. Results: The majority of confirmatory findings from SiGN ( PITX2 and ZFHX3 for CE and HDAC9 for LAA) were evident in both models and in both the union and intersection of the subtyping systems. Some findings ( TSPAN2 in LAA) showed up best in the intersection with stronger corresponding p-values and odds ratios whereas other findings (12q24 for SAO) appear stronger in all of the union analyses, but were also evident in intersection analyses. We identify 16 potential novel loci, 6 of which appear in numerous analyses. Conclusion: Both expanding and refining stroke subtypes may help in the identification of additional stroke genetic risk variants and should be considered as complementary to a single classification system. We are pursuing replication of the novel findings.

Introduction: Outcomes from endovascular procedures are highly dependent on the experience and skill of the operating physician. The multi-disciplinary CREST-2 Interventional Management Committee (IMC) was charged with credentialing a cohort of skilled interventionists with adequate contemporary case volumes. Methods: Applicants were required to submit 25 consecutive cases completed within 5 years as primary operator out of a required total experience of ≥ 50 cases (≥ 20 for operators completing training). Interventionists not approved on initial review were asked to submit additional cases (with procedural angiograms), the number depending on quality and recent-quantity of the cases. Results: The IMC has had 102 meetings, and 283 interventionists have been evaluated: 104 (37%) interventionists were cardiologists, 64 (23%) vascular surgeons, 42 (15%) neurosurgeons, 32 (11%) neuroradiologists, 26 (9%) neurologists, 9 (3%) interventional radiologists, and 6 (2%) other. The mean total experience among the 226 interventionists with available information was 220±263 carotid stent cases (median 135; range 10-2500). A total of 7037 cases have been reviewed by the IMC, dating from August 2001 to April 2016, with 3366 symptomatic, 3541 asymptomatic and 130 undetermined. The range of cases reviewed per interventionist was 5 to 50. Of the 251 interventionists with sufficient periprocedural follow-up data, no stroke events were reported by 152 (60.5%), and at least one or more stroke events were reported by 99 (39.5%). The IMC has approved 115 interventionists, 29 at the first review and 86 subsequently, based upon submission and review of 631 additional contemporary cases (mean=7 cases per interventionist); 122 have approval pending submission of additional cases; 33 have been denied; 8 have been deferred; 4 have been approved for the CREST-2 Companion Registry only; and 1 is pending decision. Discussion: Rigorous evaluation and credentialing of carotid stenters in CREST-2 has been demanding, for the candidates and for the evaluators. Yet the cohort of interventionists so selected should be able to provide the high-quality stenting outcomes necessary for acceptance of the trial results.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

11503 Background: EHE is a rare vascular cancer arising in liver, lung, soft tissue and bone. The natural history of metastatic disease varies considerably from indolent growth over years to rapid growth with fatal outcome in months. Treatment of patients (pts) with metastatic EHE with antiangiogenic therapy induces tumor response in a minority of pts, and median PFS is 6-12 months. TAZ-CAMTA1 translocation results in activation of MAPK pathway and is an oncogenic driver in EHE. We sought to evaluate the effect of MEK inhibition using trametinib in pts with unresectable EHE. Methods: A phase 2 trial of trametinib 2 mg daily was conducted in pts with EHE though the Experimental Therapeutics Clinical Trials Network supported by NCI in collaboration with SARC. Additional support was provided by the EHE Rare Cancer Charity and the EHE Foundation. Pts had to have evidence of objective tumor progression or EHE-related pain requiring narcotics for relief prior to enrollment. Presence of TAZ-CAMTA1 translocation was analyzed by fusion-FISH after enrollment. Primary trial endpoint was objective response rate (ORR) per RECIST1.1 with at least 1 objective response required in the 1st 13 pts to expand enrollment to 27. The trial was amended after stage 1 to continue enrollment to 27 pts with TAZ-CAMTA1 detected by FISH with goal of >4 objective responses in this group. Secondary objectives were PFS and OS rates, safety and change in pt-reported global health and pain scores per PROMIS questionnaires. Results: 43 pts were enrolled between 6/2017 – 9/2020 across 10 sites and 41 started therapy. TAZ-CAMTA1 fusion was detected in 26, not detected in 7, test failed in 5 and was not performed due to insufficient tumor in 5. Median pt age was 54 (range 22-81 yrs) and 11 were >65 yrs; 25 were female; ECOG was 0 in 23, 1 in 16 and 2 in 3 pts. Most pts experienced reduction in tumor size. ORR per RECIST was 7% (3/41); in pts with TAZ-CAMTA1 detected, the ORR was 0% (0/26). Mean pain intensity and interference scores had a statistically significant improvement and global quality of life scores did not statistically change after 4 weeks of therapy. 17 pts remained on treatment > 6 months and 7 > 12 months. 25 pts stopped trametinib due to EHE progression, 6 died during treatment, 6 withdrew from treatment, 3 stopped drug due to adverse event and 1 is on treatment. The most common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea, alopecia and edema; Grade >3 AEs included anemia, dyspnea, hypoxia, hypotension, syncope and dermatitis. Conclusions: To our knowledge, this is the largest prospective clinical study focused on pts with EHE. Although the trial did not meet the ORR goal, stable disease > 6 months was seen in 40% of pts, and EHE-related pain improved on treatment. Trametinib was associated with expected cutaneous and GI adverse effects. Additional pt-reported outcomes and biomarkers of inflammation are undergoing analysis. Clinical trial information: NCT03148275.

Abstract INTRODUCTION: Retinal imaging is a non-invasive tool to study retinal vasculature and neurodegeneration. Patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD)-related cognitive disorder exhibit both retinal vascular abnormalities and intraretinal accumulation of amyloid beta-protein (Aβ) plaque. Curcumin-enhanced retinal fluorescence imaging (CRFI) was recently translated as a safe imaging tool for retinal Aβ plaque quantification, holding promise as an early-stage pathological biomarker of AD. In this exploratory study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status.METHODS: We used scanning laser ophthalmoscopy to assess quantitative CRFI in a cohort of patients with cognitive impairment that underwent standard neuropsychological testing. Retinal blood vessels were segmented in a predefined circumpapillary region of interest. For each centerline, vessel tortuosity index, vessel inflection index and branching angle was quantified. Additionally, we automatically quantified retinal amyloid count in the supero-temporal quadrant and its subregions: posterior pole, proximal mid-periphery, and distal mid-periphery. Investigators performing quantifications were blinded to the subjects’ clinical characteristics. Linear regression models were used to assess the correlations between retinal vascular and amyloid parameters and cognitive domain Z-scores.RESULTS: In this pilot study, 34 subjects underwent automated retinal amyloid imaging and 29 subjects (55% female, mean age 64±6 years) had the combined retinal amyloid and peripapillary vascular analysis. Eleven subjects had normal cognition, 15 MCI, 2 probable AD and 1 non-AD dementia. CRFI was increased in individuals with impaired versus normal cognitive function (p 0.0012). Venous VTI was the most significant vascular parameter that differ across levels of CDR. Branching angle correlated with amyloid count in the distal mid-periphery (p=0.03), whereas vessel inflexion index correlated with posterior pole amyloid count (p=0.02). The combined proximal mid-periphery amyloid count – venous tortuosity index was found to exhibit highly significant group differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs 0.91 ± 1.4, p=0.006). The combined proximal mid-periphery amyloid-venous tortuosity index also correlated with verbal memory (Wechsler Memory Scale-IV; p=0.001) and cognitive-related quality of life (SF-36 mental component score Z-scores; p=0.039).CONCLUSION: Retinal venular tortuosity discriminates across cognitive scores and in combination with proximal mid-periphery amyloid count predicts verbal memory and cognitive-related quality-of-life. Future research is needed to confirm the clinical utility of this integrated retinal imaging-based methodology.

Objective: Transoral endoscopic laser-assisted diverticulotomy (TELD) with diverticulectomy and diverticuloplasty (TELD + DD) for the management of Zenker’s diverticulum (ZD) has been utilized by our institution since 2016 in attempts to reduce residual pouch size. This technique involves complete endoscopic pouch excision with partial advancement of mucosal flaps. Our study compares the subjective outcomes, objective outcomes, and complication rates between TELD and TELD + DD. Methods: A retrospective cohort study was performed on patients who underwent TELD or TELD + DD by a single surgeon at a tertiary academic center (2013-2019). Videofluoroscopic swallow studies (VFSS) with esophagram, Eating Assessment Tool (EAT-10), Reflux Symptom Index (RSI), and Functional Outcome Swallowing Scale (FOSS) were collected at preoperative and 3 month follow-up visits. A single blinded reviewer recorded height, width, and depth of pre and postoperative pouches with volumetric analysis performed assuming an ellipsoid shape. Comorbidities, complications, postoperative course, and recurrence were recorded. Results: Of the 75 patients that met criteria, 27 underwent TELD + DD and 48 underwent TELD. Eighteen TELD + DD and 37 TELD had both pre and post-operative VFSS. TELD + DD and TELD had a 96 ± 7% and 87 ± 16% reduction in pouch volume, respectively ( t-test; P = .01). Complications (TELD + DD 7%, TELD 17%, fisher’s exact; P = .31) and final subjective outcomes after adjusting for initial were not significantly different between methods (EAT-10 with TELD + DD ∆ + 1.3, P = .18; RSI ∆ + 1.4, P = .29; FOSS ∆-0.02, P = .91). One short-term recurrence was reported with TELD. Conclusion: Use of TELD + DD is associated with a statistically significantly decreased residual pouch size with no significant difference in short-term subjective outcomes. Complication rates and short-term recurrence rates are comparable. Long-term recurrence rates will require further studies to characterize. Level of Evidence: Level 3.

AbstractObjectives/HypothesisTest a new jellyfish collagen biomaterial aimed to increase duration of injection medialization laryngoplasty (IL) against two products in clinical practice.Study DesignAnimal model.MethodsLeft recurrent laryngeal nerve sectioning and IL were performed in New Zealand White rabbits (N = 6/group). Group 1 received micronized cross‐linked jellyfish collagen (MX‐JC) and adipose derived stem cells (ADSCs), Group 2, MX‐JC alone, Group 3, cross‐linked hyaluronic acid (X‐HA), and Group 4, micronized acellular dermis (MACD). Animals were sacrificed at 4 and 12 weeks. Major outcomes were MRI tissue volumes and histopathology.ResultsAfter 100 μL IL MRI volumes (means ± STD) at 4 and 12 weeks were: Group 1: 27.2 ± 15.6 and 13.1 ± 5.2 μL, Group 2: 60.8 ± 18 and 27.8 ± 2.47 μL, Group 3: 27.4 ± 12 and 10.6 ± 8 μL, and Group 4: 37.5 ± 11 and 9.85 ± 1 μL. Group 2 volumes were largest and Group 3 were smallest in all comparisons (P < .05). Histologically, low grade inflammatory responses were observed in Group 1, mild histiocytic infiltration in Group 2, widespread muscle fiber loss in Group 3, and plasmocytic infiltration in Group 4.ConclusionsMX‐JC showed the least resorption at 4 and 12 weeks among all groups. T cell inflammatory responses were observed with MX‐JC but were reduced by 12 weeks while B cell immune responses, indicative of antibody priming, were predominantly noted with MACD. MX‐JC + ADSC showed low grade immunity while the XHA showed greater myocyte loss compared to the other groups.Level of EvidenceNA Laryngoscope, 131:E2452–E2460, 2021